The nuclear receptor (NR) superfamily of ligand regulated transcription factors has proven to be a rich source of targets for the development of therapeutics for a wide range of human diseases. The estrogen-related receptors (ERR? , ERR? and ERR?) regulate several physiological processes, including mitochondrial function, glucose and lipid metabolism, and muscle fiber type determination. While structurally related to the estrogen receptors ER? and ER?, they do not bind endogenous ER ligands. The ERR's are constitutively active orphan nuclear receptors, and while ERR? and ERR? are more ubiquitously expressed, ERR? it is more restricted to metabolically active and highly vascularized tissues such as heart, kidney, brain and skeletal muscles. ERR?-/- mice fail to thrive shortly after birth due to abnormal heart and spinal cord development, but haploinsufficient ERR?+/- mice are viable and phenotypically normal in the absence of stress. ERR?+/- mice exhibit decreased exercise capacity and muscle mitochondrial function compared to their WT littermates. In mice, muscle-specific forced expression of ERR? increased oxygen consumption, treadmill endurance, mitochondrial function and these animals were resistant to diet-induced weight gain. Interestingly, repression of ERR? expression in db/db mice ameliorated hyperglycemia via inhibition of hepatic gluconeogenesis. Given the receptors specific tissue distribution and important physiological functions, the identification of ERR?-selective small molecule modulators would be valuable chemical probes and pharmacological tools. Our goal is to optimize our current lead series of ERR? ligands with the appropriate potency, selectivity and pharmacokinetic (PK) properties to provide ERR? probes to interrogate the function of the receptor in vivo and its role in the pathophysiology of disease. In order to achieve this goal, we propose the following Specific Aims: 1) Further develop and optimize ERR?-selective ligands with improved potency, selectivity and pharmacokinetic properties; 2) Characterize the pharmacology of these ERR?-selective compounds in vitro and in vivo. Accomplishment of these Aims will provide novel, first-in-class ligands that selectively modulate ERR? activity. These probes will be useful for the study of the receptors function in vivo in animal models of disease such as obesity and type-2 diabetes, cardiovascular disease and muscle atrophy.